Controlling the Flow of Energy: Inhibition and Stimulation of the Creatine Transporter

Abstract

Creatine in its free and phosphorylated form plays an essential role for maintenance and distribution of ATP levels in tissues with high and fluctuating energy demands such as muscle, brain and heart. Alterations in the creatine concentration in these tissues produce marked functional changes. Creatine concentration is largely determined by a specific creatine transporter, a member of the Na+ dependent transporters family, that is localized on the cells' plasma membrane.This transporter is needed to carry creatine into the cells against a high concentration gradient. In recent years the mechanisms regulating the expression and the function of this transporter are being unraveled. Even if our knowledge of this matter is still limited, we have now tools for either stimulating or inhibiting this transporter, tools that may be relevant to several experimental and clinical conditions. This review will examine the data and the tools that are available in relation to the regulation and expression of the creatine transporter. Furthermore, we will briefly review the possible practical relevance of manipulating the creatine transporter activity.

In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism

“…Cr uptake in our study was greatly reduced by GPA, an inhibitor of CT1 [ 1 , 24 ], thus strongly suggesting that it mostly happens through this transporter. This functional result was supported by gene expression analysis, showing that both cell types express CT1.…”

Therapeutic Use of Creatine in Brain or Heart Ischemia: Available Data and Future Perspectives

“…Cr uptake is at least partially inhibited by prolonged exposure to high extracellular Cr levels and by increased intracellular Cr content. Moreover, no data exist on the brain content of Cr after long‐term supplementation . Therefore, although Cr administration could be attempted in this kind of patients, before designing them it would be desirable to have evidence that long‐term Cr treatment actually causes brain Cr to remain stably elevated.…”

Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

“…It is interesting to note that proteins that have been associated with regulation of CRT [270], such as the serine/threonine-protein kinases 1 and 3 (also known as serum and glucocorticoid-regulated kinases, SGK1/3), are activated upon H 2 O 2 accumulation [271], which was observed after the electrical stimulation protocol of Derave et al [269]. Other in vitro and animal studies have found that several kinases regulate CRT activity [14,268,272]. Additionally, Almeida et al (2006) demonstrated in vitro that Cr is synthesized and taken up by central neurons and released by exocytosis depending on an action potential, which implies certain mechanisms of vesicular translocation are responsible for CRT localization [273].…”

“…However, approximately 95% of the Cr pool in the body is found in skeletal muscle [11][12][13]. After synthesis, Cr reaches target tissues through the bloodstream, and intracellular transport mediated by a solute carrier protein called sodium-and chloridedependent creatine transporter (CRT, also known as SLC6A8) [14]. This symporter belongs to a family of neurotransmitter transporters known as solute carrier family 6, which has shown a high affinity to Cr in the plasmalemma (low Km, 15-77 µM) [15][16][17].…”

“…Cr and its phosphorylated form, phosphocreatine (PCr), have a critical and centralized role in maintaining adenosine triphosphate (ATP) concentrations in tissues with high-energy demands, such as skeletal muscle, heart, and brain [28]. Alterations in Cr concentrations due to CRT, AGAT, or GAMT deficiencies may produce functional changes in these tissues, leading to a wide range of diseases [14,22,[49][50][51] that are grouped into the Cr deficiency syndrome [52]. For example, CRT malfunction results in low levels of intracellular Cr, which, while not lethal, induces an impairment in brain energy metabolism to the same extent as deficiencies in the Cr biosynthesis enzymes [22,53].…”